Will zilebesiran, an RNA interference therapy, be effective, safe, and improve the treatment of hypertension?

• Published in: Expert opinion on biological therapy Vol. 24; no. 12; p. 1329
• Main Author: Doggrell, Sheila A
• Format: Journal Article
• Language: English
• Published: England 01.12.2024
• Subjects: Animals; Antihypertensive Agents - adverse effects; Antihypertensive Agents - therapeutic use; Blood Pressure - drug effects; Humans; Hypertension - drug therapy; Hypertension - genetics; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - genetics; RNA Interference; RNA interference therapy; Angiotensinogen inhibitor; clinical trials; zilebesiran; IONIS-AGT-LRx; hypertension; KARDIA-1
• ISSN: 1744-7682
• DOI: 10.1080/14712598.2024.2425343

Less than half of the subjects with hypertension have been diagnosed and treated, with only 21% having their blood pressure under control. Many of the subjects find it difficult to adhere to daily antihypertensives. Zilebesiran reduces hepatic angiotensinogen messenger RNA levels to inhibit the renin-angiotensin-aldosterone system and is being developed as a long-acting anti-hypertensive agent. KARDIA-1; a phase 2 clinical trial of zilebesiran with mild-to-moderate hypertension. Most doses of zilebesiran (150-600 mg) modestly reduced blood pressure from baseline to month 3. Adverse events included hyperkalemia and kidney failure. The main problem with zilebesiran is that it only has a modest effect on blood pressure, and it is likely to have to be used as add-on therapy, which will probably reduce any benefits on adherence it has. It was also difficult to reliably interpret the results of KARDIA-1 as blood pressure went up significantly in the placebo group. KARDIA-1 did not answer previous concerns about zilebesiran; (i) what happens during volume depletion, sepsis, and pregnancy when angiotensinogen is inhibited long term or (ii) will it be effective in a high sodium diet.